Thieno(2,3-E)(1,4)diazepine derivatives

ABSTRACT

A thieno (2,3-e)(1,4) diazepine compound of the formula:   WHEREIN Hal is a halogen atom, and Am is an -NH2 or -CONHCH3 group; and a pharmaceutically acceptable salt thereof. Hal is selected from the group consisting of F, Cl, Br and I. The compounds encompassed within the formula presented above exhibit pharmacologic activities in the form of narcosis potentiation, suppression of fighting behavior, an anticonvulsant activity, which activities permit such compounds to be employed in the treatment of anxiety neuroses, hypochrondriasis, hysteria, depression states, psychosomatic illnesses, and epilepsy.

United States Patent [191 Nakanishi et al.

[ June 3, 1975 TI-IIENO( 2,3-E) 1 ,4 )DIAZEPINE DERIVATIVES [75] Inventors: Michio Nakanishi, Oita; Masami Shiroki; Tetsuya Tahara, both of Fukuoka; Kazuhiko Araki, Fukuoka, all of Japan [73] Assignee: Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan [22] Filed: Jan. 29, 1974 [21] Appl. No.: 437,590

Related US. Application Data [63] Continuation-in-part of Ser. No. 205,765, Dec. 7,

1971, abandoned.

[30] Foreign Application Priority Data Primary Examinew-l-lenry R. Jiles Assistant ExaminerRobert T. Bond Attorney, Agent, or FirmSughrue, Rothwell, Mion, Zinn and Macpeak [57] ABSTRACT A thieno [2,3-e][l,4] diazepine compound of the formula:

wherein I-Ial is a halogen atom, and Am is an NI'I or CONI-ICH group; and a pharmaceutically acceptable salt thereof. Hal is selected from the group consisting of F, Cl, Br and l.

The compounds encompassed within the formula presented above exhibit pharmacologic activities in the form of narcosis potentiation, suppression of fighting behavior, an anti-convulsant activity, which activities permit such compounds to be employed in the treatment'of anxiety neuroses, hypochrondriasis, hysteria, depression states, psychosomatic illnesses, and epilepsy.

, 3 Claims, No Drawings 1 THIENO( 2,3-E)( l ,4 )DIAZEPINE DERIVATIVES RELATION TO OTHER PATENT APPLICATIONS This application is a continuation-in-part of Ser. No. 205,765 filed Dec. 7, 1971 now abandoned. Priority is claimed based on the Japanese priority documents submitted during the prosecution of Ser. No. 205,765.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to therapeutically valuable thieno [2,3-e][1,4] diazepine derivatives.

2. Description of the Prior Art Compounds of the formula R R H, lower alkyl, aryl, CF halogen, nitro, lower alkoxy, etc. or R and R combinedly form (CH n 3, 4,

R H, lower alkyl;

R H, lower alkyl, lower cycloalkyl', and

X H, halogen, CF lower alkoxy,

are disclosed in Netherlands patent application No. 6,918,458, German patent application No. 2,005,276 and US. patent application Ser. No. 1 16,240 (copending) as having utility as muscle relaxants, tranquilizers activity, CNS-depressants, anticonvulsants and minor tranquilizers.

SUMMARY OF THE INVENTION A thieno[2',3-e][ 1,4] diazepine compound of the formula:

wherein Hal is a halogen atom, and Am is an NH or CONHCH group; and a pharmaceutically acceptable salt thereof. Hal is selected from the group consisting of F, Cl Br and I.

The compounds encompassed within the formula presented above exhibit pharmacologic activities in the form of narcosis potentiation, supression of fighting behaviour, an anti-convulsant activity, which activities permit such compounds to be employed in the treatment of anxiety neuroses, hypochrondriasis, hysteria, depression states, psychosomatic illnesses, and epilepsy.

DETAILED DESCRIPTION OF THE INVENTION Compounds of general formula (I) can be produced by one of the following methods (i) and (ii):

i. In the case of compounds of the general formula (I) wherein Am is NH by reacting a compound of the formula with an aminating agent,

The aminating agent is, for example, a hydroxylamine derivative such as O-2,4-dinitrophenylhydroxylamine, O-mesitoylhydroxylamine or hydroxylamine- O-sulfonic acid, or a halogenated amine such as chloroamine or bromoamine.

The reaction is usually carried out in a solvent by first converting, in a solvent at a temperature of from room temperature to reflux temperature, compound (II) into an alkali metal salt with a metallating agent, such as an alkali metal (Li, Na or K) or an alkali metal compound (hydride, alkoxide or amide of an alkali metal), and then reacting the alkali metal salt with an aminating agent at a temperature of from room temperature to reflux temperature. The solvent can be, for example, benzene, toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, ethyl ether, isopropyl ether, dioxane or dimethylformamide. The time for reaction (i) and (ii) is usually about 1 to 50 hours. The pressure is generally:

reaction (i): atmospheric pressure reaction (ii): at atmospheric pressure, or at a pressure of up to about 30kg/cm (in a pressure vessel such as an autoclave or a pressure bottle), at a temperature of from about to about C.

ii. In the case of compounds of general formula (I) wherein Am is -CONHCH by reacting a compound of formula (II) with a compound of the formula:

CH NCO Ll'o or a salt thereof to intramolecular condensation.

The compounds of formula (I) can be converted into the corresponding acid addition salts in a conventional manner by treatment with various inorganic and organic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric, citric, maleic, fumaric, succinic, oxalic and tartaric acid.

The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof have excellent pharmacological actions in narcosis potentiation, suppression of fighting behavior and anticonvulsant effects as shown, for example, by the following tests.

I. Narcosis Potentiation The influence of 30 minutes pre-treatment with the test compound on the action of 40 mg/kg (sub-narcotic dose) of hexobarbital was investigated using groups of 6 male mice. The effect of narcosis potentiation by the test compound was determined by the disappearance of the righting reflex lasting for more than 30 seconds. The righting reflex was examined at 15 and 30 minutes after the administration of hexobarbital. When no reflex was observed at either time, the rate of narcosis potentiation was evaluated as 100%, and the PD (50% potentiation dose) of the test compound was determined graphically. The test compounds were all administered intraperitoneally. (Time test compound intraperitoneally administered; Time 30 minutes 40 mg/Kg of mouse weight of hexobarbital intraperitoneally administered. Time 45 minutes and Time 60 minutes: righting reflex tested.)

11. Suppression of Fighting Behavior Fighting episodes were produced in mice by the method described by Tedeschi et al. in the Journal of Pharmacology and Experimental Therapeutics, vol. 125, p. 28 ff. (1959). Groups of8 female mice (4 pairs) were given the test compound orally 60 minutes prior to receiving an electric foot-shock for 3 minutes with a 530 volt interrupted direct current, 1.3 milliampers 10 cycles per second. The exhibition of 3 fighting episodes or less within the 3 minute electric foot shock treatment was deemed to be a suppression of the fighting behavior by the test compound. 81 pairs of control mice had shown an 8.7 fighting episode average under the same conditions without administration of the test compound. The ED the dose required to suppress 50% of fighting pairs, was determined graphically.

III. Anticonvulsant Effect Pentylenetetrazole (150 mg/kg) was administered subcutaneously to groups consisting of 6 mice minutes after the intraperitoneal administration of the test compound. The number of dead mice was counted 3 hours after the administration of Pentylenetetrazole, and then the ED the dose required to suppress the mortality rate to 50%, was determined graphically. Results:

Compounds A and B are identified below:

A: 1-amino-5-o-chlorophenyl-7-ethyl-1,2-dihydro- 3H-thieno[2,3-e][1,4]diazepin-2-one B: l-methylcarbamoyl-5-o-chlorophenyl-7-ethyl-1 ,2-

dihydro-3H-thieno-[2,3-e][1,4]diazepin-2-one For discussions of above tests, see F. E. Roth et al. Archives Internationales de Pharmacodynamie et de Therapie vol. 118, p. 375 ff. (1959); and W. L. Kuhn et al. Journal of Pharmacology and Experimental Therapeutics vol. 134, p. 60 ff. (1961 In view of various tests, including those mentioned above, the compounds of the invention represented by formula (I) and pharmaceutically acceptable acid addition salts thereof can be safely administered as minor tranquilizers for the treatment of anxiety neurosis, hypochondriasis, hysteria, depressive state, psychosomatic disease, epilepsy, and the like, in the form of a pharmaceutical preparation with a suitable and conventional carrier or adjuvant, administrable orally, without harm to the patients.

The pharmaceutical preparations can take any conventional form such as tablets, capsules or powders.

FORMULATION EXAMPLE 5 mg tablets were prepared from the following compositions:

Compound (I) 5.0 mg Starch 20.0 Lactose 50.5 Methyl Cellulose 1.0 Magnesium Stearate 0.5 Talc 3.0

1% powders were prepared from the following compositions:

Compound (I) 1 Starch 18 Lactose Methyl Cellulose l The oral daily dose of compound (I) or a salt thereof for human adults usually ranges from about 10 to 30 milligrams, in single or multiple dose.

The present invention will be better understood from the following examples which are illustrative and not limitative of the present invention.

EXAMPLE 1 To a suspension of 1.4 g of sodium hydride (about 50% in mineral oil) in 50 ml of dimethylformamide there was added carefully, with stirring, 7.3 g of 5-ochlorophenyl-7-ethyl-l ,2-dihydro-3I-I-thieno[2,3- e][l,4]diazepin-2-one. The resulting suspension was stirred at 70C on a water bath for 30 minutes. After cooling, 5 g of O-2,4-dinitrophenylhydroxylamine was added at 20-25C. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, and the aqueous mixture extracted with chloroform. The chloroform extract was washed well with water and dried over magnesium sulfate, and the solvent distilled off under reduced pressure. The residue was treated with a mixture of petroleum ether and ethanol (50 ml: 5 ml) and the white crystals thus obtained were recrystallized from ethanol to give l-amino-5-o chlorophenyl-7-ethyl-l ,2-dihydro-3H-thieno[ 2,3-

e][ 1,4]diazepin-2-one, melting at l53l54C, in yield.

EXAMPLE 2 was added carefully, with stirring, 30.4 g of 5-0- 5 chlorophenyl-7-ethyl-l ,2-dihydro-3l-l-thieno[2,3-

e][l,4]diazepin-2-one.The resulting suspension was stirred at 70C on a water bath for 30 minutes. After cooling, there was added thereto 500 ml of diethyl compounds of the invention tested above are compared with the following ,test compounds 3-7. I.

The test compounds are shown below: l-amino-5-o-chlorophenyl 7 ethyl-1,2 dihydro- 3H-thieno[2,3-e][ l ,4]-diazepin-2;one (the compound of claim 2 of the invention.) B: l-methylcarbamoyl-5-o-ch1oropheny1-7-ethyl-1,2-

,dihydro-3H-thieno[2,3-e][1,4]diazepin-2-one (the yield.

compound of claim 3 of the invention) 6,7 ,8,9-tetrahydro-5-phenyll H[ l ]benzothieno[2,3-e] 1 ,4]diazepin-2( 3l-l)-one. (-the comether solution containing chloroamine at a concentra- 10 tion of 0.25 M. After stirring at room temperature for 31 l5 hours, the reaction mixture was poured into water and the aqueous mixtu-re extracted with --ether. The Pound of Claim 2 f Tinney reference) ethereal extract was washed well with water, dried over 4: 6 ,7,8,9-tetrahydro-l-methyl-S-phenyl-lH- magnesium sulfate andthe solvent distilled off. The resl5 [2,3-e][ l,4]diazepin-2(3H)-one iduewas crystallized with a mixture of petroleum ether (the compound of claim 5 of Tinney refere c and ethanol, and the white crystals thus obtained re- 51 P y y crysta lliz ed from ethanol to give l-amino-S-ol ll l P c liloroph'enylJ-ethyl-l ,2-dihydro-3H-thieno[2,3- compound of Example/5 of Tinney reference) e][ l,4] diazepin-2-one, melting at 153-154c, in 73% 61 y -p y t 1,4-diazepin-2-one (the compound of claim 7 of l-lromatka reference) 7-chloro-l ,3-dihydro-1-methyl-5-phenyl-2H- thieno[2,3-e]-l,4-diazepin-2-one (the compound of claim 13 of Hromatka reference) The results are summarized in the following Table:

' EXAMPLE 3 7:

To a solution of g of 5-o-ch1orophenyl-7-ethyl- 1,2-dihydro-3l-l-thieno[2,3-e][ 1,4]diazepin-2-one in Narcosis Potentiation Anticonvulsant The Tinney reference is US. Pat. No. 3,558,606, and the Hromatka reference is US. Pat. No. 3,669,959.

200 ml of benzene is added 4 g of methyl isocyanate, the resulting mixture is refluxed for 5 hours, an additional l g of methyl isocyanate is added, and the whole 40 mixture refluxed for an'additional 5 hours.The reaction mixture is then evaporated to dryness under reduced pressure, and the crude crystalline product recrystallized from ethanol to give l-methylcarbamoyl-S- o-chlorophenyl-7-ethyll ,2-dihydro-3H-thieno[ 2,3-

EXAMPLE 5 Comparative pharmacological testing between the l-amino and l-methylcarbamoyl derivatives of the present invention and the corresponding l-hydro derivative have been carried out as follows:

Compound I A v B C Narcosis Potentiation l.25-2.5 l.252.5 1.25-25 su g/ Suppression of Fighting Behavior ED5u mg/ kg Anticonvulsant Effect Reserpine Potentiation 80 ziu g/ g Reserpine Antagonism 80 ziu g/ no effect no effect e][l,4]diazepin-2-one as white crystals, melting at Compound: 126-l27C with decomposition.

EXAMPLE 4 Compounds of the prior art have been tested using the Narcosis Potentiation, Suppression of Fighting Be- CH havior and Anticonvulsant Effect tests described 5 above. In the following Table, the test results of the two Am A: lamino-SO-chlorophenyl-7-ethyl-1,2-dihydro- 3H-thieno[2,3-e]['l,4]diazepin-2-one (the compound of the present invention where Am Nl-l B: -1methylcarbamoyl-So-chlorophenyl-7-ethyl-l ,2-

dihydro-3l-l-thieno[2,3-e][ 1 ,4]-diazepin-2-one (the compound of the present invention where Am CONHCl-h) C: 5-o chlorophenyl-7-ethyl-l ,2-dihydro-3H- thieno[2,3-e][ l ,4]-diazepin-2-one (Am H, the l-hydro derivative) Methods:

1. The methods of testing narcosis potentiation, suppression of fighting behavior and anticonvulsant effect are as described in the present specification hereinabove.

2. The method of testing for reserpine potentiation or antagonism is based on effect of the compound on reserpine-induced ptosis is as follows:

Groups of 4 female mice each were used. According to the following criteria, the degree of palpebral ptosis of both eyes were scored at 15, 60, 120 and 180 minutes after intraperitoneal administration of reserpine (10 mg/kg):

The following scores, which were obtained as average values (iS.D.) with 30 control groups of 4 mice treated with reserpine in past experiments were used as control values (Maximum effect for each group is 32 calculated as a score of 4 times 8 eyes).

minutes later 0.33 i 0.75

60 minutes later 26.90 i 2.14 120 minutes later 31.67 10.17 180 minutes later 32.00 i 0 The test compound was administered subcutaneously to the animals 30 minutes prior to the administration of reserpine. The degree of ptosis was expressed as the measured score less the corresponding reference score at the time of measurement. Accordingly, the antagonized case was given a minus score. The dose amount which caused the total of scores with 4 animals, at 60, and 180 minutes, smaller than 27 (ca. 30% antagonism) was expressed as RD The dose amount which caused the total of scores with 4 animals at 15 minutes at 10 (ca. 30% potentiation) was expressed as PD As is seen from the data cited above, compounds A and B of the present invention exhibit more potent anticonvulsant effect (2.6-5.2 times) than compound C. Moreover, compound A exhibits reserpine potentiation while compound B exhibits reserpine antagonism. The latter fact suggests that the compound A can also be used effectively as a neuroleptic for the treatment of schizophrenia or mania, while compound B can have use as an antidepressant for the treatment of depressant states. As tabulated, the l-hydro derivative did not exhibit any significant reserpine potentiation or reserpine antagonistic effect up to a dosage level of mg/Kg.

Although the present invention has been adequately discussed in the foregoing specification and examples included therein, one readily recognizes that various changes and modifications may be made without departing from the spirit and scope thereof.

What is claimed is: l. A thieno[2,3-3][1,4]diazepine compound of the formula:

Hal

1 C N U CH CH CH wherein Hal is a halogen atom, and Am is an Nl-l or CONHCl-l group; and a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1:

lamino-S-o-chlofophenyl-7-ethyl- 1 ,2-dihydro-3l-lthieno[2,3-e][ 1,4]diazepine-2-one.

3. The compound of claim 1:

lmethylcarbamoyl-S-o-chlorophenyl-7-ethyl-l ,2- dihydro-3l-l-thieno[2,3-e][ 1,4]diazepine-2-one. 

1. A THIENO(2,3-3)(1,4)DIAZEPINE COMPOUND OF THE FORMULA:
 1. A thieno(2,3-3)(1,4)diazepine compound of the formula:
 2. The compound of claim 1: 1-amino-5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno(2,3-e)(1, 4)diazepine-2-one. 